3 - World Journal of Gastroenterology

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Sun Y et al . Terahertz pulsed imaging and spectroscopy referred to as the “THz gap”. In 1975, David Auston at AT&T Bell Laboratories developed a photoconductive emitter gated with an optical pulse that led towards bridging this gap - the ‘Auston switch’ emitted broadband THz radiation up to 1 mW. A coherent method to detect THz pulses in the time domain was also proposed [3] . This became the foundation of THz time-domain spectroscopy (THz-TDS) [4] , since then many improvements in the generation and detection of coherent THz radiation enabled THz-TDS and imaging techniques to be pioneered for applications in various fields such as biomedical engineering, physics, astronomy, security screening, communications, genetic engineering, pharmaceutical quality control and medical imaging [5] . In this paper, THz technology is introduced and some emerging applications in biology and medicine including molecular spectroscopy, tissue characterization and skin imaging are presented. The aim of this article is to review the potential of THz pulsed imaging and spectroscopy as a promising diagnostic method. Several unique features make THz very suitable for medical applications. (1) THz radiation has very low photon energy, which is insufficient to cause chemical damage to molecules, or knock particles out of atoms. Thus, it will not cause harmful ionization in biological tissues; this makes it very attractive for medical applications; (2) THz radiation is very sensitive to polar substances, such as water and hydration state. For this reason, THz waves can provide a better contrast for soft tissues than X-rays; (3) THz-TDS techniques use coherent detection to record the THz wave’s temporal electric fields, which means both the amplitude and phase of the THz wave can be obtained simultaneously. The temporal waveforms can be further Fourier transformed to give the spectra. This allows precise measurements of the refractive index and absorption coefficient of samples without resorting to the Kramers-Kronig relations; and (4) The energy of rotational and vibrational transitions of molecules lies in the THz region and intermolecular vibrations such as hydrogen bonds exhibit different spectral characteristics in the THz range. These unique spectral features can be used to distinguish between different materials or even isomers. PRINCIPLES OF THZ PULSED IMAGING AND SPECTROSCOPY THz systems Over the past two decades, technology for generating and detecting THz radiation has advanced considerably. Several commercialized systems are now available [6-10] and THz systems have been set up by many groups all over the world. According to the laser source used, THz systems can be divided into two general classes: continuous wave (CW) and pulsed. A typical CW system can produce a single fixed frequency or several discrete frequency outputs. Some of them can be tunable. Generation of CW THz radiation can be achieved by approaches such as photomixing [11] , WJR|www.wjgnet.com Laser diode1 Laser diode2 BS Emitter cw THz Sample Detector Delay Figure 1 Schematic illustration of a continuous wave THz imaging system in transmission geometry. Vitesse femtosecond pulsed laser Delay stage Probe beam Sample Quartz imaging plate Photoconductive emitter free-electron lasers [12] and quantum cascade lasers [13] . Figure 1 illustrates a CW THz system which photomixes two CW lasers in a photoconductor as an example [14] . The mixing of two above-bandgap (visible or near-infrared) wavelengths produces beating, which can modulate the conductance of a photoconductive switch at the THz difference frequency. The photomixing device is labeled “emitter” in Figure 1. Since the source spectrum of the CW system is narrow and sometimes only the intensity information is of interest, the data structures and postprocessing are relatively simple. It is possible now to drive a whole CW system by laser diodes and thus it can be made compact and inexpensive. However, due to the limited information that CW systems provide, they are sometimes confined to those applications where only features at some specific frequencies are of interest. In pulsed systems, broadband emission up to several THz can be achieved. Currently, there are a number of ways to generate and detect pulsed THz radiation, such as ultrafast switching of photoconductive antennas [3] , rectification of optical pulses in crystals [15] , rapid screening of the surface field via photoexcitation of dense electron hole plasma in semiconductors [16] and carrier tunneling in coupled double quantum well structures [17] . Among them, the most established approaches based on photoconductive antennas, where an expensive femtosecond laser is required and configured as shown in Figure 2. Unlike CW THz imaging system, coherent detection in pulsed THz imaging techniques can record THz waves in the time do- 56 March 28, 2011|Volume 3|Issue 3| 30° Photoconductive detector Pump beam Figure 2 Schematic illustration of a pulsed THz imaging system with reflection geometry.
Rotations Vibrations Water H-bonds main, including both the intensity and phase information, which can be further used to obtain more details of the target such as spectral and depth information [18] . This key advantage lends coherent THz imaging to a wider range of applications. Molecular interactions in the THz regime There has been an increased interest in understanding the interactions between molecules and THz radiation. Many of the intricate interactions on a molecular level rely on changes in biomolecular conformation of the basic units of proteins such as α helices and β sheets. In recent years, dynamic signatures of the THz frequency vibrations in RNA and DNA strands have been characterized [19,20] . Furthermore, studies of water molecule interactions with proteins have attracted significant research interest [21] . In a protein-water network, the protein’s structure and dynamics are affected by the surrounding water which is called biological water, or hydration water. As illustrated in Figure 3, hydrogen bonds, which are weak attractive forces, form between the hydrated water molecules and the side chains of protein. These affect the dynamic relaxation properties of protein and enable distinction between the hydration water layer and bulk water. The remarkable effects of the hydrogen bonds associated with the intermolecular information are able to be detected using THz spectroscopy. THz spectra contain information about intermolecular modes as well as intra-molecular bonds and thus usually carry more structural information than vibrations in the mid-infrared spectral region which tend to be dominated by intra-molecular vibrations. Unique advantages and challenges for biomedical applications The energy level of 1 THz is only about 4.14 meV (which is much less than the energy of X-rays 0.12 to 120 keV), it therefore does not pose an ionization hazard as in X-ray WJR|www.wjgnet.com Biomolecule H-bonds Figure 3 Schematic representation of H-bond interactions between water and biomolecules. Sun Y et al . Terahertz pulsed imaging and spectroscopy radiation. Research into safe levels of exposure has also been carried out through studies on keratinocytes [22] and blood leukocytes [23,24] , neither of which has revealed any detectable alterations. This non-ionizing nature is a crucial property that lends THz techniques to medical applications. The fundamental period of THz-frequency electromagnetic radiation is around 1ps, and so it is uniquely suited to investigate biological systems with mechanisms at picosecond timescales. The energy levels of THz light are very low, therefore damage to cells or tissue should be limited to generalized thermal effects, i.e. strong resonant absorption seems unlikely. From a spectroscopy standpoint, biologically important collective modes of proteins vibrate at THz frequencies, in addition, frustrated rotations and collective modes cause polar liquids (such as water) to absorb at THz frequencies. Many organic substances have characteristic absorption spectra in this frequency range [25,26] enabling research into THz spectroscopy for biomedical applications. THz wavelengths have a diffraction limited spot size consistent with the resolution of a 1990’s vintage laser printer (1.22λ0 = 170 μm at 2.160 THz or 150 dots/in). At 1 THz, the resolution could be as good as a decent computer monitor (70 dots/in). Submillimeter-wavelength means that THz signals pass through tissue with only Mie or Tyndall scattering (proportional to f 2 ) rather than much stronger Rayleigh scattering (proportional to f 4 ) that dominates in the IR and optical since cell size is less than the wavelength. Since most tissues are immersed in, dominated by, or preserved in polar liquids, the exceptionally high absorption losses at THz frequencies make penetration through biological materials of any substantial thickness infeasible. However, the same high absorption coefficient that limits penetration in tissue also promotes extreme contrast between substances with lesser or higher degrees of water content which can help to show distinctive contrast in medical imaging. IMAGING VS SPECTROSCOPY THz pulsed imaging Early applications of THz technology were confined mostly to space science [27] and molecular spectroscopy [28,29] , but interest in biomedical applications has been increasing since the first introduction of THz pulsed imaging (TPI) in 1995 by Hu and Nuss [30] . Their THz images of porcine tissue demonstrated a contrast between muscle and fats. This initial study promoted later research on the application of THz imaging to other biological samples. THz pulsed imaging actually can be viewed as an extension of the THz- TDS method. In addition to providing valuable spectral information, 2D images can be obtained with THz-TDS by spatial scanning of either the THz beam or the object itself. In this way, geometrical images of the sample can be produced to reveal its inner structures [31] . Thus, it is possible to obtain three-dimensional views of a layered structure. 57 March 28, 2011|Volume 3|Issue 3|
Page 1 and 2: World Journal of Radiology World J
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